The hippocampus, amygdala, and ventral anterior cingulate are each implicated in the pathophysiology of mood disorders. The volume of the subiculum of the hippocampus is abnormally decreased in major depressive disorder (MDD) and bipolar disorder. Subtle decreases in hippocampal volume were previously reported by some MRI studies of mood disorders, although many other studies were unable to confirm this difference. Two studies of the hippocampus performed post mortem provided clues that the reduction in volume may be confined to discreet subregions of the hippocampus, namely the subiculum and the adjacent CA1 region. The subiculum plays major roles in guiding reward-directed behavior and in modulating endocrine responses to stress. It is also the portion of the hippocampus that shares the heaviest anatomical connections with other brain regions implicated in regulating emotional behavior. A method for imaging the human brain at a very high spatial resolution, developed in collaboration between NIMH and NINDS, permitted reliable volumetric measures of the subiculum and adjacent CA1 cortex. Application of this technique revealed a marked reduction in the volume of the subiculum exists in bipolar disorder, and demonstrated this abnormality can be noninvasively detected using MRI. The amygdala has an abnormal reduction of glial cells in MDD. Glial cells were previously shown to be decreased in other brain regions of the prefrontal cortex which share extensive anatomical connections with the amygdala in both MDD and bipolar disorder. The glial cells play a variety of important roles in assisting the function of the neurons, the cells responsible for carrying signals from one brain region to another. Working in collaboration with researchers at Washington University, we were able to show that the abnormal reduction in glia in the amygdala specifically involves oligodendrocytes, which play major roles in maintaining the communication across connections between neurons. This abnormality could therefore interfere with the normal functioning of the amygdala, which plays major roles in the regulation of emotional behavior. The amygdala plays a major role in organizing and regulating the behavioral, autonomic and endocrine responses to threat or stress, and the emotional inferences that occur in response to sad or anxious facial expressions or statements. During this past year, we continued to use high resolution MRI images acquired on a high field strength magnet to investigate cerebral volumes in mood disorders. Comparisons across groups showed that the volumes of the amygdala and infralimbic cortex are decreased in depressed subjects who have developed a chronic or intermittent course (i.e., have undergone the disabling process of "cycle acceleration", in which episodes become more frequent or chronic, less responsive to treatment, more severe, and do not completely remit in the intervals between illness exacerbations.) More specifically, we were able to show that the amygdala is reduced in volume in currently depressed subjects with MDD who have followed chronic or intermittent illness courses, relative to cases who are 1) healthy controls, 2) bipolar disordered, or 3) depressed or remitted subjects with MDD but who follow an episodic course. We also demonstrated that the amygdala volume was abnormally small in bipolar disorder subjects who are unmedicated, but was above normnal in volume in bipolar disorder subjects who were being medicated with lithium. Lithium is a mood stabilizer that has been shown to have protective and trophic effects on brain cells in rats. Our data suggest these protective and trophic effects also extend to humans with bipolar disorder. This finding may provide insight into lithium's therapeutic effects as a mood stabilizer in bipolar disorder. The regions implicated in these studies are involved in emotion regulation, and our findings imply that the preservation of volume in subjects who have developed MDD may enable them to recover from depressive symptoms and maintain recovery for extended periods between episodes. These data provide important insights into the pathophysiological underpinnings of chronicity in depression. We currently are assessing genetic factors that confer vulnerability for having abnormally small volumes of the amygdala, hippocampus, and anterior cingulate cortex. In the Radke-Yarrow subject sample we completed our initial analyses. Magnetic resonance imaging was performed in 33 offspring of mothers with MDD, 25 offspring of mothers with BD, and 28 offspring of healthy women (mean age=15.5 years). Mothers also underwent MRI (healthy: n=14;MDD: n=15;BD: n=13). The corpus callosum genual (CC-genu) was the region-of primary-interest. Other CC subregions were assessed post hoc.The CC-genu was smaller in MDD and BD mothers relative to healthy mothers, and also in female offspring of the mothers with mood disorders relative to female offspring of healthy women. Similar reductions occurred in the CC-splenium. The genu and total CC areas correlated inversely with family stress in daughters, which partially mediated the association between maternal mood disorders and offspring CC area reductions. These data indicate that familial mood disorders are associated with neuromorphometric changes which arise in children before the onset of mood disorders, and that these changes are associated with stress exposure. A paper has been submitted for publication reporting these findings. This past year we discovered that a genetic mutation associated with increasing the risk for bipolar disorder is associated with reduced gray matter in the ventral striatum. This structure plays a major role in the regulation of mood, affect and reward processing. These domains are disturbed in bipolar disorder, so we have the opportunity to learn about the genetic vulnerability to this severe, disabling illness.